These goals of this study are to identify the mutations that give rise to inherited Mendelian neurodegenerative disorders in five categories (spastic paraplegia, neuromuscular disorders, movement disorders, ataxia, and non-Alzheimer dementia) and to investigate how these mutations lead to disease. During the past 5 years, there has been a fundamental shift in the approach to gene discovery from linkage analysis-based positional cloning to mutational cloning, made possible by technologies and analysis equipment that perform massively parallel sequencing of DNA. This new approach also relies on the success of the Human Genome Project that provided a template against which to compare the sequences obtained from any individual. Because the great majority of genetic diseases are caused by mutations that affect the protein sequence, this research focuses on the exome, the complete protein- coding region of the genome. The challenge of mutational cloning is to identify a pathogenic mutation in the background of thousands of benign protein changing variations in individual exomes. The proposed approach combines linkage or identity-by-descent (IBD) analysis to identify genomic regions shared by all affected family members and exome sequencing of several affected relatives to identify the variants they share in the IBD region. Advances in bioinformatics offer a stepwise filtering approach to select the likely pathogenic variants to study further. Cosegregation of the variant with disease in single families and identification of mutations in the same gene in other families provide validation that the gene is responsible for the disease. In vitro studies of the effect of the mutation on the function of the gene will be done when possible. The research takes advantage of the large collection of samples from many families ascertained, extensively characterized, and extended over the past 25 years. Continued subject accrual is a unifying feature of the proposed research; new disorders are identified, panels of subjects are developed for disease-gene verification, and genotype/phenotype correlations can be determined. Beyond the implication of gene discovery for patients who suffer from a particular disorder, each new gene contributes to our understanding of the complex protein-protein interactions involved in maintenance of the neurologic system and pathways of neurodegeneration. The findings of this research will be an important part of a systematic approach to diagnosis and the eventual treatment and prevention of these diseases.